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UniProtKB - P09871 (C1S_HUMAN)

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Protein

Complement C1s subcomponent

Gene

C1S

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4.

Catalytic activityi

Cleavage of Arg-|-Ala bond in complement component C4 to form C4a and C4b, and Lys(or Arg)-|-Lys bond in complement component C2 to form C2a and C2b: the 'classical' pathway C3 convertase.1 Publication

Enzyme regulationi

Inhibited by SERPING1.1 Publication

Kineticsi

Less efficient than MASP2 in C4 cleavage.
  1. KM=12.3 µM for complement component C2 (at 37 degrees Celsius)1 Publication
  2. KM=1.9 µM for complement component C4 (at 37 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi60Calcium1
    Metal bindingi68Calcium1
    Metal bindingi113Calcium1
    Metal bindingi131Calcium1
    Metal bindingi132Calcium; via carbonyl oxygen1
    Metal bindingi134Calcium1
    Metal bindingi149Calcium1
    Metal bindingi150Calcium; via carbonyl oxygen1
    Metal bindingi153Calcium; via carbonyl oxygen1
    Active sitei475Charge relay system1
    Active sitei529Charge relay system1
    Active sitei632Charge relay system1

    GO - Molecular functioni

    • calcium ion binding Source: InterPro
    • identical protein binding Source: IntAct
    • serine-type endopeptidase activity Source: UniProtKB
    View the complete GO annotation on QuickGO ...

    GO - Biological processi

    View the complete GO annotation on QuickGO ...

    Keywordsi

    Molecular functionHydrolase, Protease, Serine protease
    Biological processComplement pathway, Immunity, Innate immunity
    LigandCalcium, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.4.21.42 2681
    ReactomeiR-HSA-166663 Initial triggering of complement
    R-HSA-173623 Classical antibody-mediated complement activation
    R-HSA-977606 Regulation of Complement cascade
    SABIO-RKiP09871

    Protein family/group databases

    MEROPSiS01.193

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Complement C1s subcomponent (EC:3.4.21.42)
    Alternative name(s):
    C1 esterase
    Complement component 1 subcomponent s
    Cleaved into the following 2 chains:
    Complement C1s subcomponent heavy chain
    Complement C1s subcomponent light chain
    Gene namesi
    Name:C1S
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
    Proteomesi
    • UP000005640 Componenti: Chromosome 12

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000182326.14
    HGNCiHGNC:1247 C1S
    MIMi120580 gene
    neXtProtiNX_P09871

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Pathology & Biotechi

    Involvement in diseasei

    Complement component C1s deficiency (C1SD)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis.
    See also OMIM:613783
    Ehlers-Danlos syndrome, periodontal type, 2 (EDSPD2)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSPD2 is characterized by the association of typical features of Ehlers-Danlos syndrome with gingival recession and severe early-onset periodontal disease, leading to premature loss of permanent teeth. EDSPD2 transmission pattern is consistent with autosomal dominant inheritance.
    See also OMIM:617174
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_077120294C → R in EDSPD2. 1 PublicationCorresponds to variant dbSNP:rs886040975EnsemblClinVar.1
    Natural variantiVAR_077121316Missing in EDSPD2; unknown pathological significance. 1 Publication1

    Keywords - Diseasei

    Disease mutation, Ehlers-Danlos syndrome

    Organism-specific databases

    DisGeNETi716
    MalaCardsiC1S
    MIMi613783 phenotype
    617174 phenotype
    OpenTargetsiENSG00000182326
    Orphaneti169147 Immunodeficiency due to an early component of complement deficiency
    PharmGKBiPA25636

    Chemistry databases

    ChEMBLiCHEMBL3913
    DrugBankiDB00054 Abciximab
    DB00051 Adalimumab
    DB00074 Basiliximab
    DB06404 C1 Esterase Inhibitor (Human)
    DB09228 C1 Esterase Inhibitor (Recombinant)
    DB00002 Cetuximab
    DB00005 Etanercept
    DB00056 Gemtuzumab ozogamicin
    DB00078 Ibritumomab tiuxetan
    DB00075 Muromonab
    DB00073 Rituximab
    DB00072 Trastuzumab
    GuidetoPHARMACOLOGYi2335

    Polymorphism and mutation databases

    BioMutaiC1S
    DMDMi115205

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Signal peptidei1 – 151 PublicationAdd BLAST15
    ChainiPRO_000002758616 – 688Complement C1s subcomponentAdd BLAST673
    ChainiPRO_000002758716 – 437Complement C1s subcomponent heavy chainAdd BLAST422
    ChainiPRO_0000027588438 – 688Complement C1s subcomponent light chainAdd BLAST251

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi65 ↔ 831 Publication
    Disulfide bondi135 ↔ 1471 Publication
    Disulfide bondi143 ↔ 1561 Publication
    Modified residuei149(3R)-3-hydroxyasparagine1 Publication1
    Disulfide bondi158 ↔ 1711 Publication
    Glycosylationi174N-linked (GlcNAc...) asparagine2 Publications1
    Disulfide bondi175 ↔ 2021 Publication
    Disulfide bondi234 ↔ 2511 Publication
    Disulfide bondi294 ↔ 3411 Publication
    Disulfide bondi321 ↔ 3541 Publication
    Disulfide bondi359 ↔ 4031 Publication
    Disulfide bondi386 ↔ 4211 Publication
    Glycosylationi406N-linked (GlcNAc...) asparagine3 Publications1
    Disulfide bondi425 ↔ 549Interchain (between heavy and light chains)PROSITE-ProRule annotation1 Publication
    Disulfide bondi595 ↔ 6181 Publication
    Disulfide bondi628 ↔ 6591 Publication

    Post-translational modificationi

    The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Hydroxylation

    Proteomic databases

    MaxQBiP09871
    PaxDbiP09871
    PeptideAtlasiP09871
    PRIDEiP09871
    ProteomicsDBi52270

    2D gel databases

    SWISS-2DPAGEiP09871

    PTM databases

    iPTMnetiP09871
    PhosphoSitePlusiP09871

    Miscellaneous databases

    PMAP-CutDBiP09871

    Expressioni

    Gene expression databases

    BgeeiENSG00000182326
    ExpressionAtlasiP09871 baseline and differential
    GenevisibleiP09871 HS

    Organism-specific databases

    HPAiCAB016722
    HPA018852

    Interactioni

    Subunit structurei

    C1 is a calcium-dependent trimolecular complex of C1q, C1r and C1s in the molar ration of 1:2:2. Activated C1s is an disulfide-linked heterodimer of a heavy chain and a light chain.1 Publication

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • identical protein binding Source: IntAct
    View the complete GO annotation on QuickGO ...

    Protein-protein interaction databases

    BioGridi107177, 7 interactors
    IntActiP09871, 9 interactors
    MINTiP09871
    STRINGi9606.ENSP00000328173

    Chemistry databases

    BindingDBiP09871

    Structurei

    Secondary structure

    1688
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi19 – 24Combined sources6
    Turni26 – 29Combined sources4
    Beta strandi34 – 43Combined sources10
    Beta strandi48 – 58Combined sources11
    Helixi63 – 65Combined sources3
    Beta strandi67 – 73Combined sources7
    Beta strandi75 – 77Combined sources3
    Beta strandi80 – 82Combined sources3
    Beta strandi84 – 86Combined sources3
    Beta strandi96 – 112Combined sources17
    Beta strandi122 – 131Combined sources10
    Turni134 – 136Combined sources3
    Beta strandi137 – 140Combined sources4
    Beta strandi143 – 150Combined sources8
    Beta strandi153 – 157Combined sources5
    Beta strandi162 – 164Combined sources3
    Beta strandi171 – 173Combined sources3
    Beta strandi176 – 180Combined sources5
    Beta strandi182 – 188Combined sources7
    Turni190 – 193Combined sources4
    Beta strandi201 – 207Combined sources7
    Beta strandi212 – 217Combined sources6
    Helixi220 – 222Combined sources3
    Beta strandi223 – 225Combined sources3
    Beta strandi235 – 242Combined sources8
    Beta strandi245 – 250Combined sources6
    Beta strandi252 – 254Combined sources3
    Beta strandi259 – 262Combined sources4
    Beta strandi265 – 273Combined sources9
    Beta strandi282 – 291Combined sources10
    Beta strandi300 – 306Combined sources7
    Beta strandi309 – 312Combined sources4
    Beta strandi316 – 321Combined sources6
    Beta strandi325 – 331Combined sources7
    Beta strandi334 – 341Combined sources8
    Turni348 – 351Combined sources4
    Beta strandi353 – 356Combined sources4
    Beta strandi368 – 370Combined sources3
    Beta strandi381 – 386Combined sources6
    Turni388 – 390Combined sources3
    Beta strandi391 – 393Combined sources3
    Beta strandi395 – 397Combined sources3
    Beta strandi399 – 403Combined sources5
    Turni405 – 407Combined sources3
    Beta strandi409 – 411Combined sources3
    Turni412 – 414Combined sources3
    Beta strandi421 – 423Combined sources3
    Helixi446 – 448Combined sources3
    Beta strandi452 – 455Combined sources4
    Turni456 – 459Combined sources4
    Beta strandi460 – 466Combined sources7
    Beta strandi469 – 472Combined sources4
    Helixi474 – 477Combined sources4
    Beta strandi490 – 492Combined sources3
    Helixi494 – 499Combined sources6
    Beta strandi505 – 510Combined sources6
    Helixi520 – 522Combined sources3
    Beta strandi531 – 537Combined sources7
    Helixi555 – 557Combined sources3
    Beta strandi564 – 570Combined sources7
    Beta strandi576 – 578Combined sources3
    Beta strandi583 – 590Combined sources8
    Helixi592 – 596Combined sources5
    Beta strandi616 – 620Combined sources5
    Helixi627 – 629Combined sources3
    Beta strandi635 – 639Combined sources5
    Beta strandi647 – 655Combined sources9
    Beta strandi661 – 667Combined sources7
    Helixi668 – 671Combined sources4
    Helixi672 – 681Combined sources10

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    		PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1ELVX-ray1.70A356-688[»]
    1NZIX-ray1.50A/B16-174[»]
    4J1YX-ray2.66A/B292-688[»]
    4LMFX-ray2.92A/B/C/D17-292[»]
    4LORX-ray2.50A17-292[»]
    4LOSX-ray2.00A172-358[»]
    4LOTX-ray2.92A175-423[»]
    6F1CX-ray4.20B/D16-292[»]
    6F1HX-ray4.50B/D17-292[»]
    ProteinModelPortaliP09871
    SMRiP09871
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP09871

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini16 – 130CUB 1PROSITE-ProRule annotationAdd BLAST115
    Domaini131 – 172EGF-like; calcium-bindingAdd BLAST42
    Domaini175 – 290CUB 2PROSITE-ProRule annotationAdd BLAST116
    Domaini292 – 356Sushi 1PROSITE-ProRule annotationAdd BLAST65
    Domaini357 – 423Sushi 2PROSITE-ProRule annotationAdd BLAST67
    Domaini438 – 680Peptidase S1PROSITE-ProRule annotationAdd BLAST243

    Sequence similaritiesi

    Belongs to the peptidase S1 family.PROSITE-ProRule annotation

    Keywords - Domaini

    EGF-like domain, Repeat, Signal, Sushi

    Phylogenomic databases

    eggNOGiKOG3627 Eukaryota
    COG5640 LUCA
    GeneTreeiENSGT00760000118890
    HOVERGENiHBG000559
    InParanoidiP09871
    KOiK01331
    OMAiFGPYCGN
    OrthoDBiEOG091G02DS
    PhylomeDBiP09871
    TreeFamiTF330373

    Family and domain databases

    CDDicd00033 CCP, 2 hits
    cd00041 CUB, 2 hits
    cd00190 Tryp_SPc, 1 hit
    Gene3Di2.60.120.290, 2 hits
    InterProiView protein in InterPro
    IPR035708 Complement_C1s_subcomponent
    IPR000859 CUB_dom
    IPR001881 EGF-like_Ca-bd_dom
    IPR000152 EGF-type_Asp/Asn_hydroxyl_site
    IPR018097 EGF_Ca-bd_CS
    IPR009003 Peptidase_S1_PA
    IPR001314 Peptidase_S1A
    IPR035914 Sperma_CUB_dom_sf
    IPR035976 Sushi/SCR/CCP_sf
    IPR000436 Sushi_SCR_CCP_dom
    IPR001254 Trypsin_dom
    IPR033116 TRYPSIN_SER
    PANTHERiPTHR24255:SF18 PTHR24255:SF18, 1 hit
    PfamiView protein in Pfam
    PF00431 CUB, 2 hits
    PF00084 Sushi, 2 hits
    PF00089 Trypsin, 1 hit
    PRINTSiPR00722 CHYMOTRYPSIN
    SMARTiView protein in SMART
    SM00032 CCP, 2 hits
    SM00042 CUB, 2 hits
    SM00179 EGF_CA, 1 hit
    SM00020 Tryp_SPc, 1 hit
    SUPFAMiSSF49854 SSF49854, 2 hits
    SSF50494 SSF50494, 1 hit
    SSF57535 SSF57535, 2 hits
    PROSITEiView protein in PROSITE
    PS00010 ASX_HYDROXYL, 1 hit
    PS01180 CUB, 2 hits
    PS01187 EGF_CA, 1 hit
    PS50923 SUSHI, 2 hits
    PS50240 TRYPSIN_DOM, 1 hit
    PS00135 TRYPSIN_SER, 1 hit

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P09871-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MWCIVLFSLL AWVYAEPTMY GEILSPNYPQ AYPSEVEKSW DIEVPEGYGI 
            60         70         80         90        100
    HLYFTHLDIE LSENCAYDSV QIISGDTEEG RLCGQRSSNN PHSPIVEEFQ 
           110        120        130        140        150
    VPYNKLQVIF KSDFSNEERF TGFAAYYVAT DINECTDFVD VPCSHFCNNF 
           160        170        180        190        200
    IGGYFCSCPP EYFLHDDMKN CGVNCSGDVF TALIGEIASP NYPKPYPENS 
           210        220        230        240        250
    RCEYQIRLEK GFQVVVTLRR EDFDVEAADS AGNCLDSLVF VAGDRQFGPY 
           260        270        280        290        300
    CGHGFPGPLN IETKSNALDI IFQTDLTGQK KGWKLRYHGD PMPCPKEDTP 
           310        320        330        340        350
    NSVWEPAKAK YVFRDVVQIT CLDGFEVVEG RVGATSFYST CQSNGKWSNS 
           360        370        380        390        400
    KLKCQPVDCG IPESIENGKV EDPESTLFGS VIRYTCEEPY YYMENGGGGE 
           410        420        430        440        450
    YHCAGNGSWV NEVLGPELPK CVPVCGVPRE PFEEKQRIIG GSDADIKNFP 
           460        470        480        490        500
    WQVFFDNPWA GGALINEYWV LTAAHVVEGN REPTMYVGST SVQTSRLAKS 
           510        520        530        540        550
    KMLTPEHVFI HPGWKLLEVP EGRTNFDNDI ALVRLKDPVK MGPTVSPICL 
           560        570        580        590        600
    PGTSSDYNLM DGDLGLISGW GRTEKRDRAV RLKAARLPVA PLRKCKEVKV 
           610        620        630        640        650
    EKPTADAEAY VFTPNMICAG GEKGMDSCKG DSGGAFAVQD PNDKTKFYAA 
           660        670        680 
    GLVSWGPQCG TYGLYTRVKN YVDWIMKTMQ ENSTPRED
    Length:688
    Mass (Da):76,684
    Last modified:July 1, 1989 - v1
    Checksum:i85522647A4C47205
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti294C → K AA sequence (PubMed:3007145).Curated1
    Sequence conflicti513G → GG (PubMed:2553984).Curated1
    Sequence conflicti573T → A AA sequence (PubMed:6362661).Curated1
    Sequence conflicti645 – 646TK → GR AA sequence (PubMed:6362661).Curated2

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_033643119R → H. Corresponds to variant dbSNP:rs12146727Ensembl.1
    Natural variantiVAR_077120294C → R in EDSPD2. 1 PublicationCorresponds to variant dbSNP:rs886040975EnsemblClinVar.1
    Natural variantiVAR_077121316Missing in EDSPD2; unknown pathological significance. 1 Publication1
    Natural variantiVAR_033644327V → L. Corresponds to variant dbSNP:rs2239170Ensembl.1
    Natural variantiVAR_014565383R → H. Corresponds to variant dbSNP:rs20573Ensembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    		X06596 mRNA Translation: CAA29817.1
    M18767 mRNA Translation: AAA51853.1
    J04080 mRNA Translation: AAA51852.1
    CH471116 Genomic DNA Translation: EAW88689.1
    CH471116 Genomic DNA Translation: EAW88690.1
    BC056903 mRNA Translation: AAH56903.1
    AB009076 Genomic DNA Translation: BAA86864.1
    CCDSiCCDS31735.1
    PIRiA40496 C1HUS
    RefSeqiNP_001333779.1, NM_001346850.1
    NP_001725.1, NM_001734.4
    NP_958850.1, NM_201442.3
    XP_005253817.1, XM_005253760.1
    UniGeneiHs.458355

    Genome annotation databases

    EnsembliENST00000328916; ENSP00000328173; ENSG00000182326
    ENST00000360817; ENSP00000354057; ENSG00000182326
    ENST00000406697; ENSP00000385035; ENSG00000182326
    GeneIDi716
    KEGGihsa:716
    UCSCiuc001qsj.4 human

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiC1S_HUMAN
    AccessioniPrimary (citable) accession number: P09871
    Secondary accession number(s): D3DUT4
    , Q9UCU7, Q9UCU8, Q9UCU9, Q9UCV0, Q9UCV1, Q9UCV2, Q9UCV3, Q9UCV4, Q9UCV5, Q9UM14
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1989
    Last sequence update: July 1, 1989
    Last modified: June 20, 2018
    This is version 223 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 12
      Human chromosome 12: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Peptidase families
      Classification of peptidase families and list of entries
    7. SIMILARITY comments
      Index of protein domains and families

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